JPH03275664A - Sulfonylalkylcarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:The sulfonylalkylcarboxylic acid derivative of formula I [Ar is aromatic heterocyclic group or group of formula II (X is 2-6C alkylene which may contain O and/or carbonyl in the chain); R<1> and R<2> are 1-10C alkyl; R<3> is H or 1-4C alkyl; n is 1 or 2] and its salt. EXAMPLE:4-(N,N-dipentylcarbamoyl)-5-(1-oxo-1,2,3,4-tetrahydro-6-naphth ylsulfonyl) pentanoic acid. USE:It exhibits cholecystokinin-receptor antagonistic action and is useful as a preventive and remedy for irritative colitis, biliary dyskinesia, acute pancreatitis, etc. PREPARATION:The compound of formula I can he produced by reacting an amine of formlula V to a reaction product of a thiol of formula III and a compound of formula IV (A and B are cyano, etc.) and subjecting the obtained compound of formula VI (R<4> is 1-4C alkyl) to oxidation with an oxidizing agent, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to sulfonylalkylcarboxylic acid derivatives useful as pharmaceuticals.

More specifically, the present invention provides cholecystokinin (
Cholecystokinin (hereinafter referred to as CCK) exhibits receptor antagonistic action and is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. A group represented by the formula (wherein X is a straight or branched alkylene group having 2 to 6 carbon atoms, which may contain an oxygen atom, a carbonyl group, or both at the same time in the chain), and R ' and R
2 may be the same or different, each having a carbon number of 1 to
10 linear or branched alkyl groups R
3 is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms, and n is 1 or 2].

Conventional technology CC contains gastrin, secretin (
It is a typical gastrointestinal hormone along with secretin.
In particular, it is known to be a hormone involved in exocrine pancreatic secretion stimulation, gallbladder contraction, etc.

In recent years, research on CCK has progressed, and the involvement of CCK in various diseases has been elucidated.

As a result, specific, competitive, and reversible CCK receptor antagonists are expected to be used as preventive and therapeutic agents for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis, and are attracting attention.

Since it was reported that proglumide represented by the formula, which is used as a treatment for peptic ulcers, exhibits CCK receptor antagonistic activity, research on progelmide derivatives has been progressing, and so far several CCK receptor antagonistic effects have been carried out.
Compounds having receptor antagonistic effects on C have been produced and reported (Japanese Patent Application Laid-Open Nos. 61-44855 and 62-1812).
46, 63-27468, 63-165352, 63-201156, BP-^1-0308885, ε
P-^2-0272228.1l1087103869
, 88105774, 89102431).

All of these compounds are derivatives of amino acids such as glutamic acid or aspartic acid, and the compounds of the present invention have completely different structures from these compounds.

Problems to be Solved by the Invention An object of the present invention is to provide a sulfonylalkylcarboxylic acid derivative that has a receptor antagonistic effect on CC and is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis. It is to be.

Means for Solving the Problems As a result of intensive research to find new compounds that have CCK receptor antagonistic activity, the present inventors found that certain sulfonylalkylcarboxylic acid derivatives have strong CCK receptor antagonistic activity; The present inventors have discovered that the present invention is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis.

The sulfonylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention competitively antagonizes the binding of CCK-8 to the CCK receptor, and is effective against irritable colitis, biliary dyskinesia, acute pancreatitis, etc. It is useful as a prophylactic and therapeutic agent for the following diseases.

In the definition of Ar in the general formula (I) of the present invention, the aromatic heterocyclic group is an aromatic 5- to 6-membered ring or condensed ring heterocyclic group, such as a pyridyl group, a quinolyl group, an isoquinolyl group. , thienyl group, furyl group, pyrrolyl group, indolyl group, intridinyl group, etc.

In addition, the group represented by the formula (X in the formula has the same meaning as above) is a phenyl group condensed with a cyclic compound that may contain an oxygen atom, a carbonyl group, or both at the same time in the ring, For example, indanyl group, 2゜3-dihydrobenzofuranyl group, 1-oxoindanyl group, 2-oxoindanyl group, 2,3-dihydro-2=oxobenzofuranyl group, 2,3-dihydro-3-oxobenzofuranyl group, Nyl group, 5
, 6.7.8-tetrahydronaphthyl group, chromanyl group, isochromanyl group, 1-oxo-1,2,3,4-tetrahydronaphthyl group, 2-oxo-1,2,3,4-
Tetrahydronaphthyl group, 2-oxochromanyl group, 3
-oxochromanyl group, 4-oxochromanyl group, 1-
Examples include an oxoisochromanyl group, a 3-oxoisochromanyl group, and a 4-oxoisochromanyl group.

The sulfonylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention is a novel compound, and can be produced as follows.

That is, arylthio represented by the general formula (R4 in the formula is a linear or branched alkyl group having 1 to 4 carbon atoms, and ^r, Rl, R2 and n have the same meanings as above) It can be produced by oxidizing an alkylcarboxylic acid derivative using an appropriate oxidizing agent and, if necessary, hydrolyzing it.

The compound of the general formula (III) used as a starting material in the method for producing the compound of the general formula (I) of the present invention is a new compound, and can be produced as follows.

That is, thiols represented by the general formula () (8r in the formula has the same meaning as above) and the general formula (A and B in the formula are each a cyano group or a carbon number 2
~5 alkoxycarbonyl group, or 8 is an alkoxycarbonyl group having 2 to 5 carbon atoms, B is a carboxyl group or an alkali metal salt thereof, and n has the same meaning as above). A compound represented by the general formula (^r, ASB and n in the formula have the same meanings as above) is produced by reaction in the presence of a Lewis base or Lewis acid catalyst, and if necessary, this is treated with an appropriate By performing hydrolysis and monoesterification according to the method, the general formula (^r, R' and n in the formula have the same meanings as above)
A compound represented by is obtained.

This compound or a reactive functional derivative thereof and
By reacting with an amine represented by the general formula (R' and R2 have the same meanings as above), the general formula (I)
Compounds of can be produced.

In order to suitably carry out the method for producing the compound of general formula (I) of the present invention, the compound of general formula (III) is dissolved in an inert organic solvent, such as methylene chloride, and under cooling, the compound is dissolved in a 2-fold molar to slightly excess amount. An oxidizing agent such as m-chloroperbenzoic acid is added in an amount, preferably 2.5 times the mole, and the mixture is stirred for 2 to 3 hours under cooling or at room temperature. ), in which R3 is a linear or branched alkyl group having 1 to 4 carbon atoms. Next, by hydrolyzing this according to a conventional method, the general formula (
A compound of I) in which R3 is a hydrogen atom is obtained.

The sulfonylalkylcarboxylic acid derivative represented by the general formula (I) of the present invention has an asymmetric carbon, and there are two types of optically active forms. Either mixture can be used.

Further, the carboxylic acids in which R3 is a hydrogen atom in the compound of general formula (I) of the present invention can be converted into pharmacologically acceptable salts according to conventional methods. Such as, for example, inorganic salts such as sodium salts, calcium salts, etc.
Organic salts such as morpholine salts, piperidine salts or salts with amino acids can be mentioned. Furthermore, -a
When Ar in the compound of formula (I) is a nitrogen-containing heterocyclic group such as a quinolyl group, it can also be converted into an acid addition salt such as a hydrochloride or a sulfate. These pharmacologically acceptable salts also have receptor antagonistic effects on CC and are useful as prophylactic and therapeutic agents for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis.

When the sulfonylalkylcarboxylic acid derivative represented by general formula (1) of the present invention is used as an actual therapeutic agent, it can be administered orally as a suitable pharmaceutical composition, such as a tablet, powder, granule, capsule, or injection. Administered parenterally. These pharmaceutical compositions are prepared by conventional pharmaceutical techniques.

The dosage is determined appropriately depending on the gender, age, weight, type of disease, severity of symptoms, etc. of the target patient, but in the case of oral administration, it is approximately 1 to 1000 cm per adult molar, and in the case of parenteral administration, it is approximately 1. It is administered within the range of 0.1 to 100 μ per day.

EXAMPLES The contents of the present invention will be explained in further detail with reference to the following reference examples and examples. Note that the melting points of the compounds in each Reference Example and Examples are all uncorrected.

Reference Example 1 1.07 g of 1-oxo-1,2,3,4-tetrahydro-6-naphthalenethiol pionic acid and 0.55 ml of 2-methylenegeltalonitrile were dissolved in ethanol 2o-, and Triton B (40% Methanol solution> Add 1 drop, then 4
The mixture was heated to reflux for an hour. After concentrating the reaction solution under reduced pressure, the residue was subjected to silica gel flash column chromatography (elution solvent: methylene chloride/diethyl ether/hexane=
5/1/1) to produce an oily 2-(1-oxo-1,
2,3,4-tetrahydro-6-naphthylthiomethyl)
1.49 g of geltalonitrile was used.

IR (neat): S/CM 2240 cm-
'C-a 1670 cm-' NMR (CDC13) δ: 2.0-2.3 (4H, m), 2.45-2.
75 (4H, m).

2.85-3.05 (3H, fil), 3.19 (
IH, dd, J=7.1.13.7)12),
3.33(I) I, dd, J=6.6°13.
7) 1z), 7.2 to 7.35 (2H, m),
7.99(1)1°d, J=8.2Hz) 2-(l-oxo-1,2,3,4-tetrahydro-6
1.40 g of -naphthylthiomethyl)geltalonitrile was dissolved in 10 ml of acetic acid, 5r111 of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 10 hours. The reaction solution was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added to the residue, which was washed with diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and the residue was recrystallized from diethyl ether-hexane to give 2-(I
1.25 g of -oxo-1,2,3,4-tetrahydro-6-naphthylthiomethyl>glutaric acid was obtained.

Elemental analysis value: (as C,sH+5Oss)C%
H% Calculated value 59.61 5.63 Actual value 59.60 5.58 IR (KBr): vc-o 1695.167
0 c+yr'NMR (DMSO-ds) δ: 1,7-2.7 (9H, m), 2.91 (
2H,t, J=6.0)1z), 3.16(I
H, dd, J = 8.8.13.2Hz).

3.27 (IH, dd, J=5.5.13.2Hz
), 7.15-7.35 (2H, m>, 7.7
6 (LH, d, J=8.8Hz).

12J4(2H, br 5) 2-(1-oxo-1,2,3,4-tetrahydro-6
-Naphthylthiomethyl> 1.03 g of glutaric acid was dissolved in 10 ml of methanol, 10 ml of p-toluenesulfonic acid was added, and the mixture was reacted at 40° C. for 4 hours. After concentrating the reaction solution under reduced pressure, the residue was subjected to silica gel flash column chromatography (elution solvent: chloroform/ethanol = 10/
1) to obtain 1.16 g of oily 2-(2-methoxycarbonylethyl)-3-(1-oxo-1,2,3,4-tetrahydro-6-naphthylthio)propionic acid.

IR (neat): vc-o 1730.163
0 cm-'NMR (CDCI, ) δ: 1.95-2.2 (4) 1. m>, 2.35
~2.55 (2H, m).

2.63 (2H, t, J=6.0Hz), 2.7~
2.85(1,)I.

m), 2.92 (2H, t, J=6.0Hz)
, 3.10 (IH.

dd, J=6.6.13.7Hz), 3.33
(1)1. dd, J=7.7.13.7)1z
), 3.67 (3H, s), 7.14 (1K.

d, J=1.7Hz), 7.19(IH, dd
, J=1.7°8, 2Hz), 7.94 (
11 (, d, J=8.2Hz) Reference Example 2 The compounds shown in the table (oil) were produced in the same manner as in Reference Example 1.

Ar-8CH2CH-(CH2)2-CO0CEi3
OOH Reference Example 3 0.49 g of 2-quinolinthiol and 0.5 g of sodium 3-methoxycarbonyl-2-methylenepropionate (I
Dissolve g in methanol 30-g and add Triton B (40%
After adding NO drops of methanol solution, the mixture was heated under reflux for 20 #f. The reaction solution was concentrated under reduced pressure, neutralized with 1N hydrochloric acid, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography (elution solvent: chloroform/methanol = 10/1) to obtain oily 2-methoxycarbonylmethyl-3-(2-quinolylthio>propion*). 0.11 g was obtained.

IR (neat): νc, o 1735.171
0 cm-'NMR (CDCI, ) δ: 2.74 (IH, dd, J=4.9.16.5
Hz), 2.93 (IH, dd, J=7.7.16
．． 5Hz), 3.25-3.45 (2H, m), 3
．． 68 (3L s>, 3.93 (1) 1. dd.

J-3, 3, 13, 7Hz), 7.24 (LH
, d, J8, 2Hz), 7.4-8.05
(5)1. m) Reference example 4 2- (2-methoxycarbonylethyl) -3-(1
-Oxo-1,2,3,4-tetrahydro-6-naphthylthio>propion 1i 20.60g dried benzene 5
0.26r111 of thionyl chloride was added to the mixture, and the mixture was heated under reflux for 2 hours.

The reaction solution was concentrated to dryness under reduced pressure to obtain an oily residue. A solution of this residue in dry methylene chloride (5 ml) was added dropwise to a solution of 0.36 ml of dipentylamine and 0.25 ml of triethylamine in 5 ml of dry methylene chloride under water cooling and stirring, and the mixture was reacted at room temperature for 11 hours. The reaction solution was washed successively with dilute hydrochloric acid, water, an aqueous sodium bicarbonate solution, and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel flash column chromatography (elution solvent: methylene chloride/diethyl ether/
Hexane=1/1/2) to refine the oily 4-(N,N
-dibentylcarbamoyl)-5-(1-oxo-1,
0.58 g of methyl 2,3,4-tetrahydro-6-naphthylthio>pentanoate was obtained.

IR(neat): ”CmO1730,1675,
1635Cm-'NMR (CDC13) δ: 0.80 (3H, t, J=7.1Hz), 0
．． 89 (3H, t, J=7.1)1z), 1.0-
1.65 (12) 1. m>, 1.9-2, 5 (6)
1. m), 2.62 (2H, t, J=6.0Hz
).

2.9N21(,t, J=6.01(z), 2.9
5-3.45 (7H.

m), 3.67 (3H, s), 7. INLH,d,
J=1.7Hz), 7.15(18,dd, J=
1.7.8.2Hz).

7.93 (IH, d, J=8.2) 1z) Reference example 5 The compounds shown in the table (oil) were produced in the same manner as in Reference Example 4.

Reference Example 6 Pancreatic 11ccK receptor binding test method by [:hang] [Molecular Pharmacol.
A pancreatic tissue membrane specimen was prepared according to the method described in vol. 3Q, p. 212, 986]. Wistar
r) The pancreas was removed from male rats, the adipose tissue was removed, and 50 times the wet weight of ice-cold 5Q d) squirrel (Tri) was removed.
s) After being shredded in HCI buffer (pH 7, 4, 37°C), it was homogenized using an ultradisperser. The homogenate was centrifuged at 50,000 x g for 10 minutes, and the precipitate was dissolved in Tris). The suspension was suspended in ICI buffer and centrifuged again at 50,000 x g for 10 minutes. Analysis buffer (50mM) Lis HCI, 5m
M MgCl2.5 mM dithiothreitol, 2■/
The precipitate was resuspended in 1 ml bovine serum albumin, 0.14 μl/ml bacitracin, and used as CCK binding test material.

Pancreatic tissue membrane suspension (usually 0.5 ■ original tissue weight / -> 30
pM (51) CCK-8, the test drug or its solvent (for total binding), and 10-6M CCK-8 (for non-specific binding) were added to the analysis buffer to give a total volume of 1-.

After incubating for 30 minutes at 37°C, the sample was filtered by suction, the filter was washed with ice-cold Tris-HCI buffer, and the filter was washed with ice-cold Tris-HCI buffer.
The radioactivity was measured using -h'779- (Packard 5650).

The amount of specific binding to the CCK receptor is determined from the difference between the total amount of binding and the amount of non-specific binding, and ICs is determined from the inhibition rate of the amount of specific binding by the test drug. The value was calculated.

Compound C1251) Control of CCK-8 binding C3° (μM) 0.25 76 6.7 6.1 Example 1 4-(N,N-dibentylcarbamoyl) -5-(1
-Oxo-1,2,3,4-tetrahydro-6-naphthylsulfonyExample 3 4-(N,N-dipentyl Rubamoyl)-5-(1-
5 g of methyl 7-1.2,3.4-tetrahydro-6-naphthylsulfonyl) pentanoate in ethanol?
RNl, 1N hydroxide) IJium aqueous solution 0.
7rn1 was added and reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, acidified with dilute hydrochloric acid, extracted with methylene chloride, and dried over anhydrous magnesium sulfate.

After distilling off the solvent under reduced pressure, the residue was subjected to silica gel flash column chromatography (elution solvent: chloroform/
4-(N,
N-dipentyl(rubamoyl)-5=(1-oxo-1
, 0.26 g of 2,3,4-tetrahydro-6-naphthylsulfonyl)pentanoic acid was obtained.

Elemental analysis value: (as C2eLsNOeS) C%
H% N% Calculated value 63.26 7.96 2.84 Actual value 63.21 7.72 2.811R (KBr
): C-01710, 1685, 1630cm
-'νso 1165 cm-' NMR (CDC1,) δ: 0.8B (3H, t, J・7.1Hz),
0.94 (3H, t, J=7.1Hz),
1.15-2.45 (18)1. m), 2.7
2 (2H.

t, J=6.6Hz), 2.95-3.55
(8H, m).

3.79 (IH, dd, J=8.2.13.7Hz
), 7.75-7, 9 (2H, m>, 8.17
(LH, d, J=7.7Hz) Example 4 The compounds shown in the table were produced in the same manner as in Example 3.

(CH2) n-CO2H Effects of the Invention The sulfonylalkylcarboxylic acid derivative represented by formula (I) of the present invention exhibits competitive CCK receptor antagonism.

For example, in a binding assay (Binding As5a, y) for the CCK receptor of isolated rat pancreas using CCK-8 labeled with 2
X10-' ~ 7 X10-' Approximately 50% at molar concentration
exerts a suppressive effect.

Thus, the compound of general formula (I) of the present invention has competitive CCK receptor antagonistic activity and is useful as a prophylactic and therapeutic agent for diseases such as irritable colitis, biliary dyskinesia, and acute pancreatitis.

Claims (3)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Ar in the formula is an aromatic heterocyclic group or formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (X in the formula is an oxygen atom in the chain. , a carbonyl group, or a linear or branched alkylene group having 2 to 6 carbon atoms which may contain both at the same time), and R^1 and R^2 may be the same or different. Good too,
Each is a linear or branched alkyl group having 1 to 10 carbon atoms, and R^3 is a hydrogen atom or a C1 to 4 alkyl group.
is a linear or branched alkyl group, and n is 1
or 2] and pharmacologically acceptable salts thereof. (2) Ar is 1-oxo-1,2,3,4-tetrahydronaphthyl group, 5,6,7,8-tetrahydronaphthyl group, 2,3-dihydro-2,2-dimethyl-3-oxobenzofuran The sulfonylalkylcarboxylic acid derivative according to claim 1, which is a nyl group or a quinolyl group, and a pharmacologically acceptable salt thereof. (3) Claim 1 or 2 represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Ar, R^1, R^2 and n in the formula have the same meanings as above) The sulfonylalkylcarboxylic acid derivatives and their pharmacologically acceptable salts as described in 2.